Pemetrexed disodium is a new multitargeted antifolate with excellent anti-cancer activity applied to various solid cancers such as non-small cell lung cancer (NSCLC), malignant pleural mesothelioma, breast cancer, colon cancer, uterine cancer, head and neck cancer, and bladder cancer. Alimta (trademark) has been used in the clinical field as a lyophilized injectable formulation. Alimta is administered in combination with cisplatin to a patient with malignant pleural mesothelioma who has not been received chemotherapy and is not eligible for surgery. Since 2007, it has also been used as a single administration to locally advanced breast cancer or NSCLC patients after chemotherapy.
Most lyophilized injectable formulations are currently used by preparing a lyophilized powder due to the instability of a drug in an aqueous solution and reconstituting the powder with physiological saline or water for injection before injection to a patient. However, the reconstitution is a cumbersome process in that a desired amount of saline or water should be weighed and poured into a vial, and has the risk of microbial contamination and a limitation in that the reconstituted formulation must be used within a certain period of time. Further, the lyophilized formulation has a high production cost and a complex manufacturing process due to a long drying cycle during the lyophilization. Therefore, in considering the production cost and user convenience, there is a need for a ready-to-use liquid formulation with stability.
However, pemetrexed is rapidly oxidized in an aqueous solution and as a result, produces various related compounds. For a drug unstable in liquid, a representative method of increasing the stability thereof is to add an antioxidant or to remove dissolved oxygen. As examples of using an antioxidant, WO2001/56575 discloses a liquid formulation including pemetrexed and an antioxidant such as monothioglycerol, L-cysteine, or thioglycolic acid. KR 10-1260636 discloses that acetyl cysteine is used as an antioxidant and citric acid is used as a buffering agent, so as to provide a formulation with increased stability for pemetrexed. However, it would be preferable to minimize the use of additives for preparing a medicine for its safety. Particularly, unidentified degradation products caused from the antioxidant and oxidative degradation products of the antioxidant itself may be formed. WO2012/121523 discloses a preparation method to increase stability by controlling dissolved oxygen concentration (DOC) in an injectable solution to be 1 ppm or lower without using an antioxidant. However, the preparation method disclosed in the document can be carried out in a lab scale but has many difficulties in a commercial scale. Particularly, in the case that water for injection or an aqueous solution, which has been degassed, is dispensed into a glass vial in a commercial scale, it is very difficult to maintain the degassed state. Therefore, the process could prevent oxidation to increase stability without using an antioxidant, but could hardly be scaled up to a commercial manufacturing process.